Targeting interferon regulatory factor 5 (IRF5) activation with a peptide inhibitor ameliorates clinical lupus in MRL/lpr mice

Abstract

Abstract Systemic lupus erythematosus (SLE) is associated with high levels of inflammatory cytokines as well as increased autoantibodies. Accumulating evidence show that loss and/or inhibition of the transcription factor interferon regulatory factor 5 (Irf5) ameliorates disease severity. Previously, we characterized a peptide inhibitor targeting Irf5 activation in the NZB/W F1 murine model of lupus and showed therapeutic protection when treated before disease onset. Here, we expanded our study to include a clinical treatment arm in the MRL/lpr lupus model after disease onset. 8 week-old MRL/lpr female mice were IP-injected with PBS or inhibitor at a dose of 100ug/mouse/injection on D0, D1, D4, D7 and D14. Proteinuria was monitored weekly; serum auto-antibodies were measured by ANA-HEp-2; anti-dsDNA IgG by ELISA, and kidney pathology was assessed. Blood was collected weekly to examine Irf5 expression and activation in immune cell subsets by imaging flow cytometry. At 8 weeks-old and before treatment, MRL/lpr mice were positive for anti-nuclear antibodies (ANA). At week 17, IgG and IgM staining on HEp-2 cells showed stronger fluorescence intensity in the control group (p=0.0053 for IgG; p<0.0001 for IgM). Serum anti-dsDNA IgG levels were also higher in the control group (782179 ± 337490 U/mL, n=7) as compared to treated (385947 ± 156487 U/mL, n=9). By week 17, 2 out of 9 mice in the control group had died, while all mice in the treated group survived. Proteinuria and body weights remained similar between groups. Data indicate that direct inhibition of murine Irf5 in multiple lupus models (NZB/W F1 and MRL/lpr) ameliorates disease severity. The inhibitor was also well-tolerated supporting the therapeutic utility of IRF5 inhibitors in the clinic.